Huntington's disease (HD) is a progressive and ultimately fatal neurodegenerative disease that afflicts about 30000 people in the USA and has no effective treatment. HD is caused by a CAG expansion within the huntingtin gene. Pathological hallmarks of HD are neuronal accumulation of soluble and aggregated misfolded huntingtin protein and neuronal degeneration primarily involving striatum and neocortex. There is accumulating evidence that soluble oligomers of mutant huntingtin protein (mhtt) are important mediators of HD pathogenesis. Our long-term objective is to define the role of mhtt oligomers in HD and to determine if interventions that decrease oligomer levels are neuroprotective in HD mice and provide an effective target for treating human HD. We have preliminary data demonstrating that some oligomers of mutant huntingtin form via site-specific oxidation of cysteine residues. These findings have led us to hypothesize that oxidation-dependent mhtt oligomers are important mediators of HD. In this proposal we plan to address the role of these oligomeric species in the pathogenesis of HD. In Aim 1 we will determine how HD progression is modified by blocking or accelerating mutant huntingtin dimerization in mouse striatum. Our hypothesis is that dimerization of mutant huntingtin promotes HD progression. We will use a lentiviral system to generate mice expressing forms of mutant N171-82Q huntingtin that dimerize or are dimerization resistant and evaluate behavioral, biochemical and anatomic disease outcomes. In Aim 2 we will screen using a cell culture system for a thiol transferase enzyme(s) that promotes conversion of soluble oligomeric huntingtin to monomer. We hypothesize that a thiol transferase that promotes this conversion will also secondarily result in decreased mutant huntingtin levels. The proposed studies will advance our understanding of the mechanisms underlying neurodegeneration in HD and could lead to the identification of new therapeutic targets. Because protein oligomers have been implicated in mechanisms underlying several neurodegenerative disorders, the proposed research could also shed light on these diseases.